We propose to study prostaglandin (PG) metabolism and its alterations in obese and non-obese Koletsky hypertensive rats (KHR). Evidence that abnormalities in PG metabolism precede the development of hypertension in spontaneously hypertensive rats (SHR) warrant study of relative contributions made by the two most potent PG metabolites - the vasoconstrictor thromboxane A2 (TXA2), and the vasodilator prostacyclin. Direct measurement of these metabolites is now possible by a technique employing high pressure liquid chromatography and electron-capture gas chromatography. Both the direct measurement and radioimmunoassay will be applied to the study of renal and vascular systems in the two models of genetic hypertensive rats and in Wistar-Kyoto normotensive controls. In the KHR PG metabolism has not yet been studied, but novel abnormalities are anticipated because of demonstrated essential fatty acid deficiency not existing in SHR. Two radioactive substrates ((1-14C)-PGH2 and (3H8)-arachidonic acid) will be used to assess alterations in rates of PG synthesis and degradation in the hypertensive as compared to normotensive rats and in the biosynthetic step at which the abnormalities occur. PG release from aortic vessels and kidneys will be measured in perfusion studies with and without pharmacological agents. The relative synthesis of TXA2 and prostacyclin will be assessed from the amount of the transfer of the radiolabelled PGH2 from platelets to vascular wall during platelet aggregation. Importantly, the ratio of TXA2 to prostacyclin in the arterial wall of the obese vs the non-obese KHR will be determined to address the question whether it relates to hypothesized platelet aggregation in the pathogenesis of atherosclerosis and/or the regulation of the contractility of the arteries of the obese KHR. Further, the KHR will provide details which will aid in assessing contribution of PG metabolites to the unique pathologic features of hypertension in this strain of genetic hypertension. Subsequent experiments could be planned to further explore the specifics of this biochemical abnormality and its eventual control.